Structure-activity and structure-side-effect relationships for the quinolone antibacterials.

The fluoroquinolones represent a major class of antibacterials with great therapeutic potential. Over the years, several structure-activity and side-effect relationships have been developed, covering thousands of analogues, in an effort to improve overall antimicrobial efficacy while reducing undesirable side-effects. In this review, the various structural features of the quinolones which govern antibacterial efficacy and influence the side-effect profile are delineated and summarized at the molecular level. Those features which most remarkably enhance antimicrobial effectiveness are: a halogen (F or Cl) at the 8-position which improves oral absorption and activity against anaerobes; an alkylated pyrrolidine or piperazine at C7 which increases serum half-life and potency vs Gram-positive bacteria; and a cyclopropyl group at N1 and an amino substituent at C5, both of which improve overall potency. Some side-effects of the quinolones are class effects, and cannot be modulated by molecular variation. These include gastrointestinal irritation and arthropathy. Several other potential side-effects are directly influenced by structural modification. For example, CNS effects and drug interactions with theophylline and NSAIDs are strongly influenced by the C7 substituent with simple pyrrolidines and piperazines the worst actors. Increasing steric bulk through alkylation ameliorates these effects. Phototoxicity is determined by the nature of the 8-position substituent with halogen causing the greatest photo reaction while hydrogen and methoxy show little light induced toxicity. Genetic toxicity is controlled in additive fashion by the choice of groups at the 1, 7 and 8 positions. From the analysis, those groups which mutually improve efficacy while reducing side-effects are identified. In addition, preclinical models for determining potential side-effects are discussed.